BIOTECH: Key to long-term immune response discovered

La Jolla Institute scientists' work could lead to better vaccines

LA JOLLA -- A gene that helps make disease-fighting antibodies
has been identified by a research team headed by a scientist from
the La Jolla Institute for Allergy & Immunology.

The discovery, which could lead to development of better,
longer-lasting vaccines, was published online Thursday in the
prominent journal Science.

The work required unraveling the extremely intricate biochemical
mechanisms that cause a bewildering variety of immunity-producing
cells to proliferate.

Shane Crotty of the institute headed a team that found the basic
step that leads to producing disease-fighting chemicals called
antibodies.

They discovered a gene that controls formation of a certain kind
of white blood cell called TFH.

This is one out of five "flavors" of white blood cells
collectively called CD4, Crotty said.

Although the work was performed in mice, their immune system is
similar to that of humans, Crotty said, so the research is
applicable to human vaccine development.

Antibodies naturally provide long-term protection against some
diseases, such as measles or chickenpox.

But antibodies against some other diseases, notably influenza
and the common cold, only work for a short while.

Understanding how antibodies are made could illuminate how to
make longer-lasting vaccines.

What CD4 cells do

CD4 cells are "the center for the immune system," the body's
natural defense mechanism, said Dr. Noah Friedman, an immunologist
at Kaiser Permanente in San Diego.

These cells stimulate production of other white blood cells that
directly fight invading microbes by physically destroying them or
by producing antibodies, chemicals that neutralize them.

The TFH flavor, whose existence has been doubted by some
scientists, is responsible for producing the antibody-making cells,
Crotty said.

Crotty and the other researchers, including some from Yale
University, discovered the gene that causes production of TFH
cells.

They confirmed their discovery by turning off the gene in these
cells.

In the process, they proved the once-mysterious TFH cells
actually exist and control antibody production.

"Our experiment showed that if you get rid of them, you don't
get antibody responses; therefore, this is the specialized kind of
cell you have to have for antibody response," Crotty said.

Conversely, if more of these cells are made, you get more
antibodies.

Trial and error

By illuminating the beginnings of antibody production, the
discovery will help scientists more effectively design vaccines,
Crotty said.

Antibody research is "trial and error," Crotty said, because the
exact triggers for antibodies aren't known.

That means researchers have little idea of whether a potential
vaccine will work until it's actually tested.

But as each step in the long process of making antibodies is
understood, researchers will have more success engineering
vaccines, he said.

Rafi Ahmed, director of the Emory Vaccine Center at Emory
University, said in a La Jolla Institute news release that the
discovery was an "important breakthrough."

Another scientist commenting in the news release was Pamela L.
Schwartzberg of the Cell Signaling Section of the National Human
Genome Research Institute.

"In making this discovery, Dr. Crotty and his fellow researchers
at Yale have made a major contribution that will help provide
critical insight into the processes important for successful
vaccination and effective immune responses," Schwartzberg said.

Crotty, 35, joined the La Jolla Institute in 2003 and is an
assistant member in its vaccine discovery division.

Considered a promising young researcher in vaccines, Crotty
recently received a $7.1 million grant from the National Institutes
of Health to study an antibody that fights the smallpox virus.

The disease has been wiped out, but some governments maintain
stockpiles of the virus.

The smallpox antibody could provide protection in the event of a
bioterrorism attack, researchers say.